Parathyroid hormone (PTH) is a major regulator of bone and mineral metabolism. However, the manner by which PTH regulates the compartmentalization of trabecular and cortical bone remains unknown. Two diseases of PTH excess and deficiency, primary hyperparathyroidism (PHPT) and hypoparathyroidism (HypoPT), respectively, offer a rich repository of data that suggest roles for PTH not only with regard to circulating biochemical and densitometric indices of mineral metabolism, but perhaps more importantly, for fundamental histomorphometric and structural properties of trabecular and cortical bone. The goal of this research proposal is to apply an interdisciplinary approach to determine how PTH affects compartmentalization and microarchitecture of bone in subjects with PHPT or HypoPT before and after correction of the abnormal PTH state, either by normalization of PTH levels by parathyroidectomy (PHPT) or by administration of PTH (HypoPT). The changes that we expect to see at baseline and after correction of these abnormal PTH states will allow us to attribute, in a manner not previously shown, specific features of the skeleton tha are under the ultimate control of PTH. In addition, I will investigate whether the dual actions of PTH on cortical and trabecular bone can be shifted to a unimodal, osteoanabolic one by blocking its catabolic signaling pathway by denosumab, a specific blocker of receptor activator of nuclear factor kappa B ligand (RANKL). The quantitative tools that will be used in this research project include biochemical markers of bone turnover; bone mineral density by dual-energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT); Finite Element Analysis (FEA); and Individual Trabeculae Segmentation (ITS) analysis. PUBLIC HEALTH RELEVANCE: Parathyroid hormone (PTH) is a major regulator of bone and mineral metabolism, yet the mechanisms by which PTH regulates compartmentalization and microarchitecture of bone remain unknown. The knowledge obtained in this study should help to better characterize the specific features of the skeleton that are under the ultimate control of PTH. This understanding may lead to the development of new therapeutic interventions.